The Mad Cow Disease has struck terror in all consumers of beef. What is this microbe which is neither virus nor bacteria? Is it a new form of life or is it life? They have been termed prions and refers to an abnormal cellular protein resistant to most forms of viral inactivation. No DNA or RNA (nucleic acids fundamental to all life forms) have been found with prions.
Prions is an acronym for proteinaceous infectious particles. They are the causative agents of a class of disease known as transmissible spongiform encephalopathies (TSE). Prions are a fascinating group of agents that challenge the conventional concepts of microbiology and even life. They contain no DNA or RNA and are conformational misfoldings of a normal protein. This mutated structure faciliates recruitment of other normal proteins into this abnormal structure. Prions have been implicated in several neurodegenerative diseases affecting many animals other than man. The noteriety of Mad Cow Disease, infecting cows in England, stems from the realization that the infectious agent causing the disease in the cows is the same agent causing Creutzfeld-Jakob disease in humans. Prior to this point, it was thought that each prion was species specific.
Prions infect the central nervous system. Each of different prion strains have different incubation times and attack different portions of the brain.
Current Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD) (Adopted from Global Surveillance, Diagnosis, and Therapy of Human Transmissible Spongiform Encephalopathies: Report of a WHO Consultation, February 9-11, 1998. Geneva, Switzerland)
SPORADIC Definite Diagnosed by standard neuropathological techniques; and/or immunocytochemically; and/or Western blot confirmed protease-resistant PrP; and/or presence of scrapie-associated fibrils Probable
Progressive dementia; and at least two out of the following four clinical features:
Visual or cerebellar signs
A typical EEG during any illness of any duration; and/or a positive 14-3-3 CSF assay and durationto death of<2 years
Routine investigations should not suggest an alternative diagnosis
Progressive dementia; and at least two out of the following four clinical features:
Visual or cerebellar signs
No EEG or atypical EEG and duration <2 years
Progressive cerebellar syndrome in a recipient of human cadaveric-derived pituitary hormone; or
Sporadic CJD with a recognized exposure risk; e.g. antecedent neurosurgery with dura mater implantation
FAMILIAL Definite or probable CJD plus definite or probable CJD in a first degree relative; and/or neuropsychiatric disorder plus disease-specific PrP gene mutation
TYPE (%) DISEASE MECHANISM SPORADIC (85) CJD
Unknown FAMILIAL (10-15%) CJD
PRNP mutation Human to human transmission (~1-4%) Iatrogenic CJD
Inoculation/ingestion Animal to human transmission (20% of UK cases)* Kuru
SFI-Sporadic Fatal Insomnia
FFI-Fatal Familial Insomnia
vCJD-Variant Creutzfeldt-Jakob disease
PRNP-Prion Protein Gene
BSE-Bovine Spongiform Encephalopathy
*Since 1995, 20% of huuman prion disease were classified as vCJD.
Adapted from Castellani RJ. Pathology Case Rev 2004;9:16-19.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/Immunohistochemistry/Electron Microscopy Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Slow virus INCIDENCE 1/10,000 deaths in USA Creutzfeld-Jakob disease (CJD) Sporadic type Most common subtype (85% of cases) Familial type 10-15% of cases Iatrogenic type <5% of cases results from transmission of the causative agent via medical or surgical treatment using accidentally contaminated materials, e.g. surgical instruments. AGE RANGE-MEDIAN Creutzfeld-Jakob disease (CJD) Humans Sporadic type Individuals between the age of 50 and 75 EPIDEMIOLOGIC ASSOCIATIONS KURU Associated with cannibalism of the New Guinea Fore tribe
Infected brains were eaten
Establishment and maintenance of a longitudinal study of bovine spongiform encephalopathy (the ULiSES scheme).
Carson C, McKay JS, Brooks HW, Kelly DF, Stidworthy MF, Wibbelt G, Morgan KL.
Epidemiology Group, Veterinary Teaching Hospital, University of Liverpool, Leahurst, Neston, Wirral CH64 7TE, UK.
Prev Vet Med 2001 Oct 11;51(3-4):245-57 Abstract quote
This paper addresses the issues of tracing and compliance encountered in setting up and maintaining a UK-wide 5-year observational study of beef cattle.
The 5-year prospective study was initiated in 1997 to investigate the occurrence of bovine spongiform encephalopathy (BSE) in a single herd of pedigree Aberdeen Angus cattle, in which BSE had been detected at low prevalence.
The study was given the acronym ULiSES (University of Liverpool Spongiform Encephalopathy Scheme). All cattle present on the farm at the start of the scheme were registered as members of the study population (n=320), as were all calves subsequently born on the farm (n=350). Animals that were sold (n=291) were traced and monitored at destination farms. Farmers were requested to give advance notification of slaughter of any ULiSES animal and an attempt was made to collect post-mortem samples of nervous tissue, peripheral lymphoid tissue and striated muscle from all animals in the scheme at the time of slaughter, death or euthanasia. Sections of medulla were examined (by standard histopathological techniques) for the presence of spongiform change. Remaining samples were stored at -70 degrees C for future investigation by alternative tests. At the halfway point of the scheme in October 1999, 75.2% (506/673) of the study population was still alive; 42% (284) of the population was still alive on the study farm and 33% (222) was distributed on other farms throughout the UK. Complete sets of specimens had been recovered from 77% (129/167) of dead animals. All brainstem sections were negative by histopathological examination. No suspect cases of BSE were reported in ULiSES animals.Failure to recover specimens occurred principally in animals which had left the study farm.
The main cause of specimen loss was a failure of compliance in a small number of individuals who had purchased large numbers of ULiSES animals, and subsequently slaughtered them without contacting the University. Despite this, farmer compliance was generally high. The ULiSES scheme shows the feasibility of a country-wide longitudinal observational study spanning a period of several years and indicates the large impact of small numbers of non-compliant individuals.
Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion.
Llewelyn CA, Hewitt PE, Knight RS, Amar K, Cousens S, Mackenzie J, Will RG.
National Blood Service, Cambridge Centre, Cambridge CB2 2PT, UK.
Lancet. 2004 Feb 7;363(9407):417-21. Abstract quote
BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease caused by infection with the agent of bovine spongiform encephalopathy (BSE). Epidemiological evidence does not suggest that sporadic CJD is transmitted from person to person via blood transfusion, but this evidence may not apply to vCJD. We aimed to identify whether vCJD is transmissible through blood transfusion.
METHODS: The national CJD surveillance unit reported all cases of probable or definite vCJD to the UK blood services, which searched for donation records at blood centres and hospitals. Information on named recipients and donors was provided to the surveillance unit to establish if any matches existed between recipients or donors and the database of cases of vCJD. Recipients were also flagged at the UK Office of National Statistics to establish date and cause of death.
FINDINGS: 48 individuals were identified as having received a labile blood component from a total of 15 donors who later became vCJD cases and appeared on the surveillance unit's register. One of these recipients was identified as developing symptoms of vCJD 6.5 years after receiving a transfusion of red cells donated by an individual 3.5 years before the donor developed symptoms of vCJD.
INTERPRETATION: Our findings raise the possibility that this infection was transfusion transmitted. Infection in the recipient could have been due to past dietary exposure to the BSE agent. However, the age of the patient was well beyond that of most vCJD cases, and the chance of observing a case of vCJD in a recipient in the absence of transfusion transmitted infection is about 1 in 15000 to 1 in 30000.
DISEASE ASSOCIATIONS CHARACTERIZATION Bovine spongiform encephalopathy (BSE, Mad Cow Disease) Cows Transmissible feline encephalopathy Cats Transimissible mink encephalopathy Mink Chronic wasting disease Elk and mule deer
PATHOGENESIS CHARACTERIZATION PrP(Sc)
Recruits normal prion protein PrP(C) into its misfolded conformation
Ultrastructural analysis reveals rod-like structures composed of the prion protein
Complement Facilitates Early Prion Pathogenesis
Klein M., Kaeser P, Schwarz P, etal.
Follicular dendritic cells accumulate PrPSc by immune complex capture by Fc-gamma receptors and binding opsonized antigens to CD21/CD35 complement receptors
Prior invasion of lymphocytes and neurons occurred either in agammaglobulinemic tg141m mice with 1 monoclonal transgenic membrane-bound mu heavy chain or tg141m+s mice with both a membrane bound and secreted form of immunoglobulin in tg141m mice
Thus B lymphocytes but not circulating antibody were necessary for neuroinvasion accumulation in the spleen
Mice lacking C3 or Bf/C2 complement components, C1qa subcomponent, or CD21/CD35 complement receptors were tested with intraperitoneal prion injections and absence of C3 or its recpetor CD21/CD35 delayed neuroinvasion about 40 days with limiting prion doses
Absence of C1q alone or the absence of C1q combined with H2-Bf/C2-/- showed no prion infectivity or PrPSc 38 days after infection with low prion doses, though wild type mice did. Splenic prion titers and PrPSc levels with larger prion inoculation were similar to wild type mice
Splenic FDCs accumulated prions without complement components but CD21/CD35 receptors are involved in the FDCs binding prions in the early phase of the disease
Cerebral amyloid in human prion disease.
Watanabe R, Duchen LW.
Department of Neuropathology, National Hospital for Neurology and Neurosurgery, Queen Square, London.
Neuropathol Appl Neurobiol. 1993 Jun;19(3):253-60. Abstract quote
The clinical and neuropathological features of 21 patients with prion disease were reviewed with special reference to the morphology and immunoreactivity of cerebral amyloid.
Six cases had a mutation at codon 102 of the prion protein (PrP) gene and in these the characteristic pathology was the formation of multicentric amyloid plaques which were stained with PrP antibody, whereas spongiform changes were absent in one and minimal in two. In one case, with a 216 base-pair insertion in the PrP gene, there was no spongiform encephalopathy (SE) but cerebellar amyloid was a prominent feature of the pathology. One case with a PrP gene mutation at codon 200 had severe SE but no amyloid. Two iatrogenic and 11 sporadic cases had SE and some form of amyloid was identified in all but three. Amyloid angiopathy and senile neuritic plaques, which stained with antibody to beta-protein, were present in familial as well as in sporadic cases, including some who were rather young to be regarded as having Alzheimer's disease. Cerebellar amyloid and degeneration of granule and Purkinje cells were particularly common findings in sporadic as well as in genetically determined cases.
This study serves to emphasize the association between prion disease and amyloid deposition in the brain. PrP is a component of some amyloid plaques in a high proportion of cases with inherited prion disease but may also be found in cases of sporadic SE without known mutations or base-pair insertions in the PrP gene.
Transmission of Scrapie by Steel-surface-bound Prions.
Flechsig E, Hegyi I, Enari M, Schwarz P, Collinge J, Weissmann C.
Mol Med 2001 Oct;7(10):679-84 Abstract quote
Background: Prions are unusually resistant to conventional disinfection procedures. An electrode used intracerebrally on a Creutzfeldt-Jakob disease (CJD) patient transmitted the disease to two patients in succession and finally to a chimpanzee, despite attempted disinfection. Concerns that surgical instruments may transmit variant CJD have been raised by the finding of PrP(Sc), a surrogate marker for infectivity, in various tissues other than brain.
Materials and Methods: Stainless steel wire was exposed to scrapie-infected brain or brain homogenate, washed exhaustively and inserted into the brain of indicator mice to measure infectivity.
Results: A contact time of 5 min with scrapie-infected mouse brain suffices to render steel wire highly infectious and insertion of infectious wire into the brain of an indicator mouse for 30 min suffices to cause disease. Infectivity bound to wires persists far longer in the brain than when injected as homogenate, which can explain the extraordinary efficiency of wire-mediated infection. No detectable amounts of PrP could be eluted with NaOH, however the presence of PrP on infectious wires was demonstrated by chemiluminescence. Several recommended sterilisation procedures inactivated wire-bound mouse prions, but exposure to 10% formaldehyde was insufficient.
Conclusions: Prions are readily and tightly bound to stainless steel surfaces and can transmit scrapie to recipient mice after short exposure times. This system mimics contaminated surgical instruments and will allow an assessment of sterilisation procedures.
Currently, the only way to confirm infection is with a brain biopsy or autopsy analysis
EEG Abnormal in most of the new patients GENETIC ASSAY Identify a polymorphism at codon 129 of the human prion gene and assay for the 14-3-3 protein MRI Pulvinar sign
Severe involvement of the dorsomedial nucleus of the thalamus
Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases.
Collie DA, Summers DM, Sellar RJ, Ironside JW, Cooper S, Zeidler M, Knight R, Will RG.
Department of Neuroradiology, Western General Hospital, Edinburgh, Scotland.
AJNR Am J Neuroradiol. 2003 Sep;24(8):1560-9. Abstract quote
BACKGROUND AND PURPOSE: Variant Creutzfeldt-Jakob disease (vCJD) is a rare but important cause of dementia and death in young patients and is causally linked to bovine spongiform encephalopathy. Symmetrical hyperintensity in the pulvinar (posterior) nuclei of the thalamus (pulvinar sign) on brain MR images was described as a specific, noninvasive, diagnostic sign of vCJD in a previous small series. This purpose of this larger study was to evaluate this sign prospectively and further define the MR imaging characteristics of vCJD.
METHODS: As part of the ongoing surveillance program in the United Kingdom, MR images of suspected cases of vCJD were collected during a 6-year period. All available images were assessed prospectively by one observer for the presence of the pulvinar sign. Images of neuropathologically confirmed cases were then assessed independently by two neuroradiologists for the degree of hyperintensity of the pulvinar on images of different MR sequences, and for the presence of abnormal hyperintensity in other areas of the brain. Discrepancies were reviewed jointly and a consensus opinion formed.
RESULTS: Prospective analysis identified the pulvinar sign in 74 of 82 cases of vCJD. In the retrospective study, the pulvinar sign, as defined by hyperintensity of the pulvinar relative to the anterior putamen, was present on seven (9%) of 75 T1-weighted, 77 (71%) of 108 T2-weighted, 47 (81%) of 58 proton density-weighted, and 30 (100%) of 30 fluid-attenuated inversion-recovery (FLAIR) images. Diffusion-weighted images were available in two cases and were positive for the pulvinar sign in one. Other features were hyperintensity of the dorsomedial thalamic nuclei (93%), caudate head (40%), and periaqueductal gray matter (83%) on FLAIR images.
CONCLUSION: In the appropriate clinical context, demonstration of the pulvinar sign on MR images is a highly accurate diagnostic sign for vCJD. FLAIR sequence is more sensitive than other sequences. Positive MR images may obviate more invasive diagnostic tests in most cases.
WESTERN BLOT CSF 14-3-3 protein analysis
Biopsy diagnosis of Creutzfeldt-Jakob disease by western blot: a case report.
Castellani RJ, Parchi P, Madoff L, Gambetti P, McKeever P.
Department of Pathology, University of Maryland School of Medicine, baltimore, USA.
Hum Pathol. 1997 May;28(5):623-6. Abstract quote
Creutzfeldt-Jakob disease is a clinically and pathologically heterogeneous disorder that often requires brain biopsy for definitive diagnosis.
We report the case of a 62-year-old man who underwent brain biopsy for progressive neurological deterioration. Histopathologically, there was minimal spongiform change that could not be unequivocally attributed to Creutzfeldt-Jakob disease. A 16 mg portion of gray matter saved frozen was subsequently analyzed by Western blot and showed definitive protease-resistant prion protein.
This case illustrates applicability, ease in interpretation, and accuracy of Western blot analysis for protease-resistant prion protein in small brain biopsy specimens. Given the importance of accurate diagnosis in suspected prion disease, we recommend that a small portion of tissue from any brain biopsy performed in this setting be kept frozen for possible biochemical studies.
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION CREUTZFELDT-JAKOB DISEASE(CJD) Humans Symptoms
Psychiatric symptoms early in the illness-depression or less often a schizophrenia-like psychosis.
Painful and persistent sensory symptoms have been experienced by half of the cases early in the illness
Ataxia and involuntary movements progressive
Patients become completely immobile and mute at death
Sporadic type Most common subtype (85% of cases), usually affects individuals between the age of 50 and 75, and is characterised by a rapidly progressive dementia. The cause of sporadic CJD remains unknown and there is no evidence of a causal link with animal TSEs. - - Familial type Familial CJD (10-15% of cases) is an inherited disease associated with a gene mutation. Iatrogenic type Iatrogenic CJD (<5% of cases) results from transmission of the causative agent via medical or surgical treatment using accidentally contaminated materials, e.g. surgical instruments. FATAL FAMILIAL INSOMNIA SYNDROME Humans
Fatal familial insomnia: behavioral and cognitive features.
Gallassi R, Morreale A, Montagna P, Cortelli P, Avoni P, Castellani R, Gambetti P, Lugaresi E.
Institute of Neurology, University of Bologna, Italy.
Neurology. 1996 Apr;46(4):935-9. Abstract quote
Fatal familial insomnia (FFI) is a familial prion disease linked to a mutation of the prion protein gene. Neuropsychological investigations in seven patients with FFI belonging to two different families showed that the main behavioral and neuropsychological features are (1) early impairment of attention and vigilance, (2) memory deficits, mainly of the working memory, (3) impairment of temporal ordering of events, and (4) a progressive dream-like state with neuropsychological and behavioral features of a confusional state. Neuropathologic examination of six patients showed prominent neuronal loss and gliosis involving the anterior ventral and mediodorsal thalamic nuclei, with additional cerebral cortical involvement in two cases. Clinicopathologic correlations indicate that FFI is associated with a neuropsychological and behavioral syndrome that is distinct from the cortical and subcortical dementias, and Wernicke-Korsakoff syndrome. These findings offer insights into the function of the thalamic nuclei and challenge the notion of thalamic dementia.
GERTSMANN-STRAUSSLER-SCHENKER Humans KURU Humans SPORADIC FATAL INSOMNIA VARIANT CREUTZFELDT-JAKOB DISEASE
Variant Creutzfeldt-Jakob disease in UK children: a national surveillance study.
Verity CM, Nicoll A, Will RG, Devereux G, Stellitano L.
PIND Surveillance Group, Addenbrooke's Hospital, Cambridge, UK.
Lancet. 2000 Oct 7;356(9237):1224-7. Abstract quote
BACKGROUND: Variant Creutzfeldt-Jakob Disease (vCJD) was first reported in 1996; the youngest patient developed symptoms at 16 years of age. We have done 3 years of prospective active surveillance for progressive intellectual and neurological deterioration (PIND) in UK children, and have searched for vCJD among the children who were reported.
METHODS: Since May, 1997, there has been active surveillance for patients younger than 16 years old with PIND by means of a monthly card sent to all UK consultant paediatricians by the British Paediatric Surveillance Unit. Clinical'details of cases of PIND are obtained from reporting paediatricians by telephone interview or site visit, and an expert group of paediatric neurologists then classifies the cases.
FINDINGS: After 3 years, 885 patients with suspected PIND have been reported. Among them were two fatal cases of definite vCJD and one case of probable vCJD; all were reported in 1999. One girl was age 12 years at onset--the youngest ever case of vCJD. No other children with the clinical features of vCJD were identified. The expert group has discussed 655 cases, of which 360 have a confirmed underlying cause, being categorised into 88 known neurodegenerative diseases.
INTERPRETATION: That this prospective active surveillance in the UK has found few children with suspected vCJD is relatively reassuring. However, 3 years is a short time to survey a disease with an unknown incubation period. Since one probable and two definite cases of vCJD were reported to the study in 1999, there is concern that more childhood cases may appear.
Prions in dermatology.
Center for Vaccine Development, University of Texas Medical Branch at Galveston (on leave from the Department of Internal Medicine [Dermatology]-Federal University of Rio de Janeiro, Brazil).
J Am Acad Dermatol 2002 May;46(5 Pt 1):790-3 Abstract quote
Prion diseases are uncommon fatal neurodegenerative disorders that have gained scientific importance as a result of the emergence of new forms of these diseases in both animals and humans.
Prions appear to be composed principally or entirely of abnormal isoforms of a host-encoded glycoprotein. There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy ("mad cow disease") has affected humans. Recent studies have demonstrated that prions can adhere easily to metal surfaces, and normal sterilization procedures are not likely to completely inactivate them. Iatrogenic transmission of prion diseases, such as Creutzfeldt-Jakob disease, was recognized after corneal transplantations, dura mater grafts, neurosurgical procedures, and the use of human hormones (growth hormone and gonadotropin).
Although bovine collagen has long been recognized as a safe and biocompatible material, dermatologists should be aware of the theoretical potential for prion transmission when materials from bovine origin and products obtained from cultured cells fed with fetal or newborn calf serum are used.
HISTOLOGICAL TYPES CHARACTERIZATION CREUTZFELDT-JAKOB DISEASE Multiple microscopic and abnormal aggregates encircled by holes are seen, resulting in a daisy-like appearance and the descriptive term "florid plaques".
The spatial patterns of prion protein deposits in Creutzfeldt-Jakob disease: comparison with beta-amyloid deposits in Alzheimer's disease.
Armstrong RA, Lantos PL, Cairns NJ.
Vision Sciences, Aston University, B4 7ET, Birmingham, UK.
Neurosci Lett. 2001 Jan 26;298(1):53-6. Abstract quote
Similar pathological processes may be involved in the deposition of extracellular proteins in the brains of patients with Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD).
Hence, this study compared the spatial patterns of prion protein (PrP) deposits in the cerebral cortex and hippocampus in cases of sporadic CJD with those of beta-amyloid (Abeta) deposits in sporadic AD. PrP and Abeta deposits were aggregated into clusters and, in 90% of brain areas in CJD and 57% in AD, the clusters were regularly distributed parallel to the tissue boundary.
In a significant proportion of cortical analyses, the mean diameter of the clusters of PrP and Abeta deposits were similar to those of the cells of origin of the cortico-cortical pathways. Abeta deposits in AD were distributed more frequently in larger-sized clusters than PrP deposits in CJD. In addition, in the hippocampus and dentate gyrus, clustering of Abeta deposits was observed in AD but PrP deposits were rare in these regions in CJD.
The size, location and distribution of the extracellular protein deposits within the cortex of both disorders was consistent with the degeneration of the cortico-cortical pathways. Furthermore, spread of the pathology along these pathways may be a pathogenic feature common to CJD and AD.
Spatial pattern of prion protein deposits in patients with sporadic Creutzfeldt-Jakob disease.
Armstrong RA, Cairns NJ, Lantos PL.
Vision Sciences, Aston University, Birmingham, UK.
Neuropathology. 2001 Mar;21(1):19-24. Abstract quote
The spatial pattern of the prion protein (PrP) deposits was studied in the cerebral cortex and cerebellum in 10 patients with sporadic Creutzfeldt-Jakob disease (CJD). In all patients the PrP deposits were aggregated into clusters and, in 90% of cortical areas and in 50% of cerebellar sections, the clusters exhibited a regular periodicity parallel to the tissue boundary; a spatial pattern also exhibited by beta-amyloid (Abeta) deposits in Alzheimer's disease (AD). In the cerebral cortex, the incidence of regular clustering of the PrP deposits was similar in the upper and lower cortical laminae.
The sizes of the PrP clusters in the upper and lower cortex were uncorrelated. No significant differences in mean cluster size of the PrP deposits were observed between brain regions.
The size, location and distribution of the PrP deposit clusters suggest that PrP deposition occurs in relation to specific anatomical pathways and supports the hypothesis that prion pathology spreads through the brain via such pathways. In addition, the data suggest that there are similarities in the pathogenesis of extracellular protein deposits in prion disease and in AD.
Quantification of the vacuolation (spongiform change) and prion protein deposition in 11 patients with sporadic Creutzfeldt-Jakob disease.
Armstrong RA, Cairns NJ, Lantos PL.
Aston University, Birmingham B4 7ET, UK.
Acta Neuropathol (Berl). 2001 Dec;102(6):591-6. Abstract quote
The vacuolation (spongiform change) and prion protein (PrP) deposition were quantified in the cerebral cortex, hippocampus and cerebellum of 11 patients with sporadic Creutzfeldt-Jakob disease (CJD). The density of the vacuolation, averaged over patients, was greatest in the occipital cortex and cerebellum and least in the dentate gyrus.
The degree of PrP deposition was similar in the different cortical areas and in the cerebellum but significantly lower in the hippocampus and absent in the dentate gyrus. There were no significant differences in the extent of the vacuolation and PrP deposition in the upper and lower cortical laminae. Vacuolation and PrP deposition in the upper cortex were both positively correlated with corresponding levels in the lower cortex. In addition, in the parietal cortex and parahippocampal gyrus, the density of the vacuolation was positively correlated with the level of PrP deposition but no such correlations were observed in the remaining areas studied.
This quantitative study suggested that: (1) the pathological changes were most severe in the occipital cortex and cerebellum, while the hippocampus was least affected, (2) the pathological changes affect the upper and lower cortical laminae, and (3) the degree of correlation between the density of the vacuolation and PrP deposition may be dependent on brain region.
VARIANT CREUTZFELDT-JAKOB DISEASE
Differences in the density and spatial distribution of florid and diffuse plaques in variant Creutzfeldt-Jakob disease (vCJD).
Armstrong RA, Lantos PL, Ironside JW, Cairns NJ.
Vision Sciences, Aston University, Birmingham, UK.
Clin Neuropathol. 2003 Sep-Oct;22(5):209-14. Abstract quote
OBJECTIVE: To determine whether in cases of variant Creutzfeldt-Jakob disease (vCJD), the florid-type plaques are derived from the diffuse plaques or whether the 2 plaque types develop independently.
MATERIAL: Blocks of frontal, parietal, occipital and temporal neocortex and cerebellar cortex from 11 cases of vCJD.
METHOD: The density, distribution and spatial pattern of the florid and diffuse plaques were determined in each brain region using spatial pattern analysis.
RESULTS: The density of the diffuse plaques was significantly greater than that of the florid plaques in most areas. The ratio of the diffuse to florid plaques varied between brain regions and was maximal in the molecular layer of the cerebellum. The densities of the florid and diffuse plaques were positively correlated in the parietal cortex, occipital cortex, the inferior temporal gyrus and the dentate gyrus. Plaque densities were not related to disease duration. In the cerebral cortex, the diffuse plaques were more commonly evenly distributed or occurred in large clusters along the cortex parallel to the pia mater compared with the florid plaques which occurred more frequently in regularly distributed clusters.
CONCLUSION: The florid plaques may not be derived from the diffuse plaques, the 2 plaque types appearing to develop independently with unique factors involved in their pathogenesis.
Quantification of vacuolation ("spongiform change"), surviving neurones and prion protein deposition in eleven cases of variant Creutzfeldt-Jakob disease.
Armstrong RA, Cairns NJ, Ironside JW, Lantos PL.
Vision Sciences, Aston University, Birmingham B4 7ET, UK.
Neuropathol Appl Neurobiol. 2002 Apr;28(2):129-35. Abstract quote
Vacuolation ("spongiform change") and prion protein (PrP) deposition were quantified in the cerebral cortex, hippocampus, dentate gyrus and molecular layer of the cerebellum in 11 cases of variant Creutzfeldt-Jakob disease (vCJD).
The density of vacuoles was greater in the cerebral cortex compared to the hippocampus, dentate gyrus and cerebellum. Within the cortex, vacuole density was significantly greater in the occipital compared to the temporal lobe and the density of surviving neurones was greatest in the occipital lobe. The density of the non-florid PrP plaques was greater in the cerebellum compared to the other brain areas. There were significantly more florid-type PrP plaques in the cerebral cortex compared to the hippocampus and the molecular layer of the cerebellum. No significant correlations were observed between the densities of the vacuoles and the PrP plaques. The densities of vacuoles in the parietal cortex and the non-florid plaques in the frontal cortex were positively correlated with the density of surviving neurones. The densities of the florid and the non-florid plaques were positively correlated in the parietal cortex, occipital cortex, inferior temporal gyrus and dentate gyrus.
The data suggest: (i) vacuolation throughout the cerebral cortex, especially in the occipital lobe, but less evident in the hippocampus and molecular layer of the cerebellum; (ii) the non-florid plaques are more common than the florid plaques and predominate in the molecular layer of the cerebellum; and (iii) either the florid plaques develop from the non-florid plaques or both types are morphological variants resulting from the same degenerative process.
The spatial patterns of prion protein deposits in cases of variant Creutzfeldt-Jakob disease.
Armstrong RA, Cairns NJ, Ironside JW, Lantos PL.
Vision Sciences, Aston University, Birmingham B4 7ET, UK.
Acta Neuropathol (Berl). 2002 Dec;104(6):665-9. Epub 2002 Aug 07. Abstract quote
The spatial patterns of the prion protein (PrP) deposits were studied in immunostained sections of areas of the cerebral cortex, hippocampus, dentate gyrus, and the molecular layer of the cerebellum in 11 cases of variant Creutzfeldt-Jakob disease (vCJD). Clustering of PrP deposits, with a regular distribution of the clusters parallel to the tissue boundary, was the most common spatial pattern observed.
Two morphological types of PrP deposit were recognised, those consisting of a condensed core (florid deposits) and those deposits lacking a condensed core (non-florid deposits). The florid and non-florid PrP deposits exhibited a different profile of spatial patterns. First, the florid deposits exhibited a regularly distributed pattern of clusters more frequently than the non-florid deposits. Second, the florid deposits formed larger clusters (greater than 1,600 micro m in diameter) less frequently than the non-florid deposits. In the areas of the cerebral cortex that exhibited a regular distribution of PrP deposit clusters, the cluster size of the deposits approximated that of the groups of cells of the cortico-cortical pathway origin in only 12% of analyses. No significant differences in the frequency of the different types of spatial pattern were observed in different brain regions, or in the cerebral cortex between the upper and lower laminae.
It was concluded that the spatial patterns of the PrP deposits in the cerebral cortex in vCJD are unlikely to reflect the degeneration of the cortico-cortical pathways as has been reported in sporadic CJD (sCJD). In addition, different factors could be involved in the development of the deposits with and without a condensed core.
Laminar distribution of the pathological changes in the cerebral cortex in variant Creutzfeldt-Jakob disease (vCJD).
Armstrong RA, Cairns NJ, Ironside JW, Lantos PL.
Vision Sciences, Aston University, Birmingham B4 7ET, UK.
Folia Neuropathol. 2002;40(4):165-71. Abstract quote
To determine the pattern of cortical degeneration in cases of variant Creutzfeldt-Jakob disease (vCJD), the laminar distribution of the vacuolation ("spongiform change"), surviving neurones, glial cell nuclei, and prion protein (PrP) deposits was studied in the frontal, parietal and temporal lobes.
The vacuolation exhibited two common patterns of distribution: either the vacuoles were present throughout the cortex or a bimodal distribution was present with peaks of density in the upper and lower cortical laminae. The distribution of the surviving neurones was highly variable in different regions; the commonest pattern being a uniform distribution with cortical depth. Glial cell nuclei were distributed largely in the lower cortical laminae. The non-florid PrP deposits exhibited either a bimodal distribution or exhibited a peak of density in the upper cortex while the florid deposits were either uniformly distributed down the cortex or were present in the upper cortical laminae.
In a significant proportion of areas, the density of the vacuoles was positively correlated with either the surviving neurones or with the glial cell nuclei. These results suggest similarities and differences in the laminar distributions of the pathogenic changes in vCJD compared with cases of sporadic CJD (sCJD). The laminar distribution of vacuoles was more extensive in vCJD than in sCJD whereas the distribution of the glial cell nuclei was similar in the two disorders. In addition, PrP deposits in sCJD were localised mainly in the lower cortical laminae while in vCJD, PrP deposits were either present in all laminae or restricted to the upper cortical laminae.
These patterns of laminar distribution suggest that the process of cortical degeneration may be distinctly different in vCJD compared with sCJD.
CHARACTERIZATION SPECIAL STAINS
Toluidine blue-O staining of prion protein deposits.
Sanchez A, Guzman A, Ortiz A, Rembao D, Espinosa B, Zenteno E, Guevara J.
Departamento de Neuropatologia, Instituto Nacional de Neurologia, Insurgentes Sur 3877, La Fama, 14269 Mexico, DF.
Histochem Cell Biol. 2001 Dec;116(6):519-24. Epub 2001 Nov 24 Abstract quote.
Prion diseases or transmissible spongiform encephalopathies are a group of fatal neurodegenerative diseases caused by an abnormal form of prion protein (PrP(sc)).
In this study, we developed a sensitive histochemical detection of PrP(sc) deposits in a Gertsmann-Straussler-Scheinker disease (GSS) patient using toluidine blue-O staining, a specific reagent to stain mucins and mucopolysaccharides. Detection of prion deposits correlated with immunohistochemistry using anti-prion antibodies. Control assays were performed using amyloid-beta (Abeta) plaques from Alzheimer's disease (AD) brains. Our results demonstrated that toluidine blue-O staining allowed to recognize 69.1+/-2.6% of the total plaques recognized by the anti-prion antibody. Furthermore, in the 15 studied brain regions from the GSS patient, toluidine blue-O revealed the same recognition pattern as anti-prion labeling. Toluidine blue-O stained specifically the prion deposits but not the Abeta plaques in AD brains. The specificity of the technique was confirmed in a Creutzfeldt-Jakob disease brain.
This method opens several possibilities for postmortem diagnoses. Our results also suggest the relevance of specific post-translational modifications of PrP(sc), identified by toluidine blue-O, that might participate in the transformation of PrP(c) to PrP(sc).
Immunohistochemical localization of 14.3.3 zeta protein in amyloid plaques in human spongiform encephalopathies.
Richard M, Biacabe AG, Streichenberger N, Ironside JW, Mohr M, Kopp N, Perret-Liaudet A.
Inserm Unite 512, Neuropharmacologie et Neurochimie, Faculte de Pharmacie, Universite Claude Bernard, 8 avenue Rockefeller, 69373 Lyon cedex 08, France.
Acta Neuropathol (Berl). 2003 Mar;105(3):296-302. Epub 2002 Nov 22. Abstract quote
The localization of 14.3.3 proteins was studied in different subtypes of brain amyloid plaques.
We examined paraffin-embedded brain sections of sporadic MV2 Creutzfeldt-Jakob disease (sCJD) with Kuru plaques, sporadic VV2 CJD with plaque-like PrP(sc) (the abnornal form of prion protein) deposits, variant CJD (vCJD) with florid plaques, Gerstmann-Straussler-Scheinker (GSS) with multicentric plaques and of Alzheimer's disease (AD) with senile plaques. Adjacent immunostaining revealed PrP(sc) and 14.3.3 zeta deposits in the same amyloid plaques in all cases of sporadic CJD and vCJD, whereas 14.3.3 zeta was not seen in amyloid plaques of GSS with A117V, P102L and D202N mutations. The same immunostaining method using anti-betaA4 and anti-14.3.3 zeta antibodies revealed no colocalization in patients with AD.
Our data suggest that 14.3.3 zeta protein could interact either with PrP or with other components of PrP(sc) deposits in CJD.
Ultrastructural analysis of the florid plaque in variant Creutzfeldt-Jakob disease.
Liberski PP, Ironside J, McCardle L, Sherring A.
Department of Molecular Biology, Chair of Oncology, Medical Academy Lodz, Poland.
Folia Neuropathol. 2000;38(4):167-70. Abstract quote
We report here the first description of florid plaques--the hallmark of variant Creutzfeldt-Jakob disease (vCJD). These plaques are composed of broad bundles of amyloid, are highly neuritic and exhibited astrocytes and microglial cells.
Collectively, they are more similar to neuritic plaques of Alzheimer's disease than to kuru plaques of kuru--Creutzfeldt-Jakob disease--Gerstmann-Straussler-Sheinker disease.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES ALZHEIMER'S DISEASE
Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease.
Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H.
Institute of Neurology, University of Vienna, and Austrian Reference Center for Human Prion Diseases, AKH, Wien.
Acta Neuropathol (Berl). 1998 Aug;96(2):116-22. Abstract quote
Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD) share clinical, neuropathological, and pathogenetic features. To investigate eventual mutual influences, we screened prominently affected neocortex from 110 neuropathologically proven CJD patients for Alzheimer-type pathology with anti-beta/A4, Bielschowsky and anti-tau (immuno)stains.
The neuropathological classification of Alzheimer-type pathology was made according to the CERAD criteria. Results were controlled by comparison with Alzheimer-type changes in sections from the same cortical areas in 110 sex- and age-matched non-demented control patients. For comparison, the control patients were also classified according to the CERAD neuropathology criteria as if they had been demented. Alzheimer-type tissue changes as in definite and probable CERAD AD occur in 10.9% of the CJD patients and 19.1% of control patients (P=0.11). The median age of CJD and control patients with CERAD AD is 72 and 68 years, respectively, which differs significantly from the median ages of 64 and 63 years, respectively, in the non-AD/CJD and non-AD control patients.
Since CERAD criteria include "presence of other neuropathological lesions likely to cause dementia", an AD diagnosis in CJD patients (all of whom are demented) is solely based on densities of neuritic plaques. Similar Alzheimer-type changes in even higher frequency, however, are also present in elderly non-demented controls.
Thus, the coexistence of Alzheimer-type pathology in CJD most likely represents an age-related change. Deposits of prion protein (PrP) frequently accumulate at the periphery of beta/A4 plaques. The presence of beta/A4 amyloid in the brain may influence PrP morphogenesis.
PROGNOSIS AND TREATMENT CHARACTERIZATION
Phenothiazines: potential management of Creutzfeldt-Jacob disease and its variants.
Amaral L, Kristiansen JE.
Unit of Mycobacteriology, Institute of Hygiene and Tropical Medicine,Universidade Nova de Lisboa, Rua Junqueira 96, 1349-008, Lisbon, Portugal
Int J Antimicrob Agents 2001 Nov;18(5):411-7 Abstract quote
Creutzfeldt-Jakob disease acquired from bovines (nvCJD) has been responsible for nearly 100 deaths in the UK and thousands more may die in the years to come. New variant CJD (nvCJD) is incurable and although clinical diagnosis is becoming more precise, the diagnosis is only certain at autopsy. Phenothiazine derivatives inhibit production of prions, the disease causing agent, in cultured neuroblastoma cells, and an advanced case of nvCJD was recently brought to remission by the use of these agents in combination with an antimalarial.
In this review we present direct and circumstantial evidence in support of a model describing the manner by which the intracellular antimicrobial activity of phenothiazines might cause the destruction of intracellular prions.
Proc Natl Acad Sci 1999;96:15137-15142.
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